PROJECT ABSTRACT Increased stiffness in large elastic arteries is a significant contributor to the progression of cardiovascular disease. Diabetic patients show accelerated large arterial stiffening at a relatively young age compared to nondiabetic subjects. Biomechanical and biochemical changes have been associated with vascular remodeling in diabetic patients. As a long-lived extracellular matrix (ECM) protein, elastin provides the elasticity necessary for cyclic deformation of the arterial wall. The cumulative effects of biochemical exposure encountered during aging and disease can greatly compromises its mechanical function. However little is known about the important pathophysiological effects of the coupled biochemical and mechanical changes on the cardiovascular system. This lack of understanding is most likely to be correlated with the understudied ECM mechanics and the lack of experimental techniques to reveal the structural, mechanical, and biochemical interactions among ECM constituents in arterial remodeling. Elastin and collagen are the major ECM constituents in large elastic arteries. The structural and mechanobiological interactions between elastin and collagen, the primary load- bearing components in the arterial wall, are important for properly functioning arteries. However in all previous structural models of arteries, interactions among ECM constituents are usually ignored. The overall goal of this proposed work is to develop a multi-scale model of ECM mechanics that biochemical modifications and ECM interactions, and use this model to study the biochemical, structural, and mechanical remodeling of arterial ECM in large elastic arteries from humans and mice with diabetes with two specific aims: Specific aim 1: Create a multi-scale structural-chemo-mechanical model of ECM mechanics that integrate the intrinsic mechanical, structural, and biochemical interactions among ECM constituents; and Specific Aim 2: Use the model to study the multi-scale mechanical, structural, and biochemical remodeling of ECM in diabetes. Consideration of the interactions between elastin and collagen is an innovative idea and may lead to a major advancement in structure-based constitutive modeling. Biochemical modifications of ECM represent an important emerging area in the field of constitutive modeling of soft biological tissues in aging and many diseases. The proposed work using a structural deterministic approach to incorporate fibrous network structure, advanced imaging technique, and rigorous mechanical testing made it possible to develop a multi- scale model of ECM mechanics and interactions. Combining with a study in diabetes, this research approach has a great potential to unravel the underlying key mechanisms of ECM remodeling. Due to the important reciprocal interactions between cells and ECM, looking at the ECM may open up new perspectives in therapeutic interventions. Results form this study will provide new understandings on the underlying mechanisms of vascular complications in diabetes, and have the potential to lead to a paradigm shift in developing prevention and therapeutics for diabetic patients. 1